Chronic myeloid leukemia is chromosome mutations [t(9:22)(q34;q11)] reciprocal translocation, where BCR-ABL fusion by chromosome 9 ABL gene and chromosome 22 BCR gene, this gene encodes a 210 kDa tyrosine kinase BCR-ABL fusion, this protein is a major cause of chronic myelogenous leukemia. C-Abl in normal haploid cells are present in the cytoplasm in the tyrosine kinase, and Bcr fused form changes, which means change from haploid tetramers, which has always been the kinase activation, causes the tumors' occurrence. Bcr in protein sequences can cause polymerization of amino acid sequence which Bcr-Abl tetrapolymerized. Due to the c-Abl play an important role in myocardial cells, if carcinogenicity inhibitor Bcr-Abl selectively developed instead of Abl inhibitor, it is expected to significantly reduce such inhibitors' wide range of side effects, such as cardiac toxicity.
In 2001, FDA approved the first receptor tyrosine kinase inhibitor (TKI) Imatinib 1, for the treatment of chronic myelogenous leukemia (CML). As the first generation of Bcr-Abl inhibitors, Imatinib has become the first line drugs to treat CML. But most patients are resistant to Imatinib. Subsequent studies showed that IM drug resistance may be related to the Abl kinase activity of gene mutation such as G250E, Q252H, Y253F, Y253H, E255K, E355G, E255V, T315A, T315I, F317L, F317V, M351T, F359V, H396P, M244V. Genetic mutation leads to decreased affinity of Imatinib and Abl kinase. Most mutation decreased the affinity of Imatinib by 5-30 times. This is the main reason of drug resistance. T315I is special, and it reduced most obviously, IC50 to 6400 nM. Recently developed Ponatinib is not only valid for the T315I, but also valid for the wild type and most mutants.
With the view of x-Ray eutectic structure of Imatinib and the Abl protein kinase, the n-methyl piperazine in the structure exposed to the solvent, the linear distance between the nitrogen atoms of the two inhibitors is about 24 au. Because of the tetramer structure of Bcr-Abl, it can be combined with 4 inhibitors. If the two inhibitors are connected with chain, it is expected to greatly enhance the affinity of Bcr-Abl, so as to play a role in selective inhibition of Bcr-Abl, while the Abl is haploid, only combined with one inhibitor, the diploid inhibitor has no impact to the affinity of the enzyme.